Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, with an incidence of one or two cases per 100,000 persons and a lifetime risk of one case per 800 persons. ALS is characterized by a progressive loss of motor neurons from the spinal cord, brain stem, and cerebral cortex, leading to paralysis and death within two to five years after diagnosis without intensive physiological support. Ten percent of ALS cases are familial forms resulting from highly penetrant, monogenic mutations that cause disease.
Little is known about the specific genes that contribute to the development of sporadic ALS. Despite the extensive study of familial ALS, including the creation of animal models, the key events in the initiation and progression of sporadic ALS remain relatively unclear. Pathologically, sporadic ALS is characterized by a loss of motor neurons from the motor cortex, brain stem, and ventral horns of the spinal cord. In addition, ubiquitinated inclusions (i.e., covalent bonds between ubiquitin and other proteins that mark the other proteins for degradation) have been observed in the lower motor neurons, although the role of the inclusions in the initiation and progression of the disease remains unclear. To date, numerous mechanisms have been implicated in the selective degradation of motor neurons in patients with sporadic ALS, including oxidative damage, excitotoxicity, apoptosis, cytoskeletal dysfunction, axonal-transport defects, inflammation, protein processing and degradation defects, mitochondrial dysfunction. See Cleveland, D. W. and Rothstein J. D., From Charcot to Lou Gherig: deciphering selection motor neuron death in ALS, Nat. Rev. Neuroscience (2) 806-819 (2001); and L. I. Pasinelli et al., Unraveling the mechanisms involved in motor neuron degeneration in ALS, Ann. Rev. Neuroscience (1) 293-299 (2000).
In addition to the relatively unknown mechanisms and initiation events linked to both sporadic and familial ALS, there are only limited treatment options. To date, there is only one Food and Drug Administration-approved pharmaceutical for the treatment of ALS, Riluzole. However, this drug only extends life by an average of three months and does not significantly improve the quality of life.
FGGY or FLJ10986 was previously reported to be generally associated with ALS in 2007. T. Dunckley et al., Whole-Genome Analysis of Sporadic Amyotrophic Lateral Sclerosis, New England Journal of Medicine (358) 775-788 (2007). However, this study's analysis showed no significant normalized differences in FGGY protein expression in spinal-cord samples in ALS patients compared to non-ALS control samples and mixed FGGY protein expression levels in other tissue samples (i.e., kidney, liver, lung, head, brain, and cerebrospinal fluid). Other studies have shown a mixture of potentially relevant associations between FGGY and sporadic ALS and no relevant and/or significant relationships between this disease and gene. See R. Fernandez-Santiago et al., No evidence of association of FLJ10986 and IPTR2 with ALS in a large German Cohort, Neurobiology of Aging (32) 551e1-551e4 (2011); H. Daoud et al., Analysis of DPP6 and FGGY as candidate genes for amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (11) 389-391 (2010); A. Chio et al., A two-stage genome-wide association study of sporadic amyotrophic lateral sclerosis, Human Molecular Genetics (18) 1524-1532 (2009); M. A. Van Es et al., Analysis of FGGY as a risk factor for sporadic amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (10) 441-447 (2009); and D. Fang et al., Clinical and genetic features of patients with sporadic amyotrophic lateral sclerosis, Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration (10) 350-354 (2009).
Taken together, there is a demonstrated need for an assessment of the FGGY contribution to ALS disease severity and progression to use this relationship to improve early diagnoses and prognoses of ALS.
The articles, treatises, patents, references, and published patent applications described above and herein are hereby incorporated by reference in their entirety for all purposes.